Cancer
Treatment
Reviews
(1990)
17, 177-182
Regional chemotherapy: techniques and clinical
different results
operative
P. Schlag Section of Surgical
Oncology, Department
Principal
of Surgery, University of Heidelberg,
considerations
for
regional
F.R.G.
chemotherapy
Most malignant solid tumors ifnot initially resistant, become unresponsive to conventional cytotoxic cancer therapy. Dose limiting side-effects contribute to the drug resistance of these tumors, but regional drug administration might overcome some of the disappointments of systemic cytotoxic chemotherapy (7, 9). Th e rationale of regional cancer chemotherapy is to use the direct approach to the tumor and thus to increase the drug concentration locally without a compromising systemic toxicity. For regional therapy of primary or secondary liver tumors, decreased systemic toxicity might be expected to be due to the metabolic activity of normal liver tissue since most drugs are metabolized in passing through the liver to the general circulation (22, 32). This first pass effect increases the possibility of administering a higher cytotoxic dose regionally than is possible by using an intravenous route. Similarly, with isolated organ perfusion a complete separation between body and tumor-bearing organ circulation is achieved (15). Due to the great technical effort and the risks involved in isolated organ perfusion, as well as other problems such as the inability ofrepeating this approach in the same patient, at present the technique is used mainly for malignant tumors of the extremities. Also, regional infusion techniques have become increasingly popular in the last few years with intraperitoneal drug administration a promising therapeutic strategy (2, 5). Most experience with regional chemotherapy is derived from primary and secondary liver tumors where it is necessary to distinguish between intra-arterial and intraportal treatment. Intra-arterial
chemotherapy
of malignant
liver
tumors
The theory behind intra-arterial chemotherapy of malignant liver tumors is the fact that these tumors normally take their blood supply from the hepatic artery (19, 22, 34). To achieve a sustained approach to the hepatic artery, an operative catheter insertion is better than repeated catheter placement by interventional radiologic techniques (33); the latter technique is compromised by a high rate of thrombosis and infections. To circumvent hepatic artery occlusion during operative catheter placement, the gastro-duodenal artery is used. A catheter positioned in this branch of the common hepatic artery does not interfere with blood flow, but ensures constant direct drug administration (27). Unfortunately, in about 50% of all patients the liver is vascularized by two or three different branches of hepatic arteries and insertion of more than one catheter is necessary in these cases to obtain 030557372/90/2&3177+06
$03.00/0
0 177
1990 Academic
Press Limited
178
P. SCHLAG
complete liver perfusion by the cytostatic drug. In principle, the implanted catheter can be connected to a completely implantable medication pump or to an injection port; both can be implanted subcutaneously and enable a direct approach to the catheter. Drug administration is directly via the implanted pump and can be given to patients with injection ports using an external pump system. There has been much discussion on the advantages and disadvantages ofport and implanted pump systems (13, 16,24). Implanted pumps are more comfortable for patients and have a low risk of thrombosis and infections. On the other hand, the implantable pumps are extremely expensive and are rather inflexible as regards drugs that can be used, drug volumes and infusion rate. Therefore, increasing numbers of port systems in combination with external pump systems are being used (3). Of greater importance is the effectiveness of intra-arterial chemotherapy. Most prospective and randomized studies have been carried out in patients with metastatic colorectal cancer. These studies have compared intra-arterial with standard intravenous chemotherapy. Most of these studies showed a clear advantage for intra-arterial chemotherapy judged on the response to treatment (26, 28). There is a significantly higher rate of tumor regressions with intra-arterial chemotherapy than with intravenous treatment. Unfortunately, this higher response rate does not result in an increase in survival. This can be partially explained by extra-hepatic recurrences. In some studies therefore intraarterial and intravenous chemotherapy were combined (12, 20). There is no evidence, however, that this technique is of any advantage. In summary, the principal advantage of regional chemotherapy compared to systemic treatment is a greater response rate but few patients profit from this due to extra-hepatic tumor spread. In future, our aim must be to find better selection criteria for patients who can benefit from intra-arterial drug administration. We have found that intra-arterial retreatment of patients who previously failed to respond to systemic chemotherapy is worthwhile (11); they had a much better prognosis than patients who were not retreated intra-arterially. This approach is clinically feasible but not satisfactory in principle. Better methods are required which allow a more precise identification between those who will and those who will not profit from intraarterial chemotherapy. One method to achieve this may be by positron emission tomography (29). This method is based on metabolism measurements in vivo. Using ‘*F-uracil, the drug accumulation in normal and tumor tissue can be calculated over time. Our experience shows that in some patients a clear advantage of intra-arterial in comparison to intravenous drug accumulation can indeed be visualized (6). In our clinic the percentage of patients who showed a higher drug accumulation in the tumor tissue after intra-arterial in comparison to intravenous therapy is rather low. Nevertheless, this method permits selection of patients who may profit from chemotherapy and those who will not. Since ‘*F-uracil imaging can calculate only drug accumulation in relation to different administration modes, the results of chemoresponsiveness can be biased by drug anabolism or catabolism. Magnetic resonance spectroscopy is a new method with which we were able to demonstrate for the first time that different metabolic pathways of 5-FU can be measured in vivo in the patient (21). Therefore, in the future this method will hopefully contribute to a better understanding of the possibilities and indications for regional chemotherapy. Intraportal There are some reports tumors. In comparison
chemotherapy
of malignant
liver
tumors
on the efficacy of intraportal chemotherapy for malignant to the intra-arterial route, however, none of these studies
liver dem-
REGIONAL
CHEMOTHERAPY
179
onstrated a clear advantage of the intraportal route, neither for response rates nor for survival (26). In animal experiments, intraportal chemotherapy even showed a significant disadvantage compared to intravenous or intra-arterial administration (25). Intraportal chemotherapy is therefore not to be recommended for the treatment of manifest malignant liver tumors. On the other hand, we know that tumor cells, especially those from colonic cancer, spread via the mesenteric vein through the portal system into the liver. To attack these floating or microscopic invasive tumor cells is the rationale behind using intraportal chemotherapy as adjuvant therapy after curative tumor resection in colon cancer patients 118). This concept seems reasonable and has become popular since a first study seemed to confirm the theory in practice (35). Unfortunately, some later studies failed to confirm these results or were inconclusive. In our own study, we have not been able to demonstrate a significant reduction of liver metastases in patients who underwent intraportal chemotherapy following curative colon cancer resection compared to patients who were treated only surgically (30). Therefore, the assumption that adjuvant intraportal chemotherapy is of value to patients with colorectal cancer is as yet unproven and subject to further investigation.
Intraperitoneal
chemotherapy
It is well known that some tumors such as ovarian carcinomas or gastric cancers spread predominantly to the peritoneal cavity. To destroy these tumor cells directly by intraperitoneal drug instillation seems an attractive idea. Since practicable catheter systems for intraperitoneal chemotherapy have been developed recently, this technique has become more popular in clinical practice. Nevertheless, due to practical difficulties concerning adequate intraperitoneal drug distribution, the definition of optimal therapeutic indications has lagged behind the theoretical knowledge about this therapy (5). This may be an explanation for the fact that convincing data on the advantages of intraperitoneal drug administration in comparison to conventional treatment modalities are not yet available. Since gastrointestinal tumors also spread intraperitoneally via the mesenteric vein, intraperitoneal chemotherapy has been used as an adjuvant treatment (23). The rationale is to achieve a high drug concentration in the peritoneal cavity as well as in the portal system as a result of peritoneal drug absorption. The preliminary data are encouraging, although the results obtained in small cohorts of patients need confirmation.
Isolated
limb
perfusion
chemotherapy
An artificial circuit can be established by means of a heart-lung machine and a surgical approach to the main vascular structures of the extremities. Since all the other important organs or organ systems can be excluded from this artificial blood circuit, high dose chemotherapy in the tumor-bearing extremity can be used (15). A tourniquet between the extracorporeal and the normal systemic blood circuit helps to prevent drug reflux. This time- and personnel-consuming sophisticated surgical technique has become the standard procedure for the treatment of recurrent malignant melanoma and advanced soft-tissue sarcoma of the extremities. In about 6076 of patients, complete tumor regression in cases with satellitosis or in-transit metastases can be expected (1, 4). The most active substance commonly used for isolated limb perfusion in malignant melanoma is melphalan.
180
P. SCHLAG
The activity can be increased if hyperthermic perfusion is used (31). Since cytostatic extremity perfusion was introduced into the treatment of locally advanced or recurrent malignant melanoma, amputation is generally no longer indicated. The importance of isolated limb perfusion for primary adjuvant treatment after surgical removal ofadvanced primary lesions is questionable (4, 8). There are, however, many studies which support the concept ofadjuvant hyperthermic limb perfusion in patients with high-risk melanoma. In our study also the 5-year recurrence-free survival of perfused high-risk melanoma patients is much better than historical control figures from the literature (17). There is at present one small randomized study which found statistically significant activity of adjuvant limb perfusion in comparison to surgery alone, but this trial is open to a number of criticisms (10). To answer the question of whether isolated limb perfusion is of any value for patients with high-risk malignant melanoma we await the results of a randomized intergroup study of the E.O.R.T.C. and W.H.O. Apart from advanced malignant melanoma of the extremities, isolated cytostatic limb perfusion is also of benefit in patients with advanced soft-tissue sarcomas of the extremities (14). The aim of a preoperative extremity perfusion is to reduce tumor volume by killing the tumor cells. This would be a prerequisite for limb-sparing operations even in advanced or recurrent sarcomas. In our experience, as well as in reported results from the literature, isolated limb perfusion does help prevent limb amputation in a considerable number of patients without affecting local recurrence and overall survival. Like most effective treatments isolated limb perfusion is not without side-effects, but these are not hematological or gastrointestinal if adequate intraoperative monitoring for leakage control is available. In our hands, indium-labelled autologous erythrocytes represent the most effective procedure for leakage control (17), but in almost all cases we expect to see erythema and sometimes neurologic disturbances, especially if cisplatin is used under hyperthermic conditions. These local side-effects can probably be reduced if individualized drug dosages according to the chemosensitivity of the tumor are administered. Unfortunately, up to the present, no practical method was available to monitor drug effects in vivo during isolated limb perfusion. Magnetic resonance spectroscopy offers this possibility by measuring high-energy phosphates and pH (21). Thus, a guideline for cell necrosis due to the cytostatic treatment could be established. We believe that based on all these new techniques and methods, regional chemotherapy can be much more individualized and concomitantly its efficiency will be improved.
References 1. Baas, P. C., Schraffordt Koops, H., Hoekstra, H. J., Oosterhuis, J. W., van der We&, L. T. & Oldhoff, J. (1988) Isolated regional perfusion in the treatment of local recurrence, satellitosis and in-transit metastases of melanomas of the extremities. Reg. Cancer Trent. 1: 33-36. 2. Brenner, D. E. (1986) Intraperitoneal chemotherapy: a review. J. Clin. Oncol. 4: 1135-l 147. 3. Civalleri, D., Cafiero, arterial chemotherapy
F., Cosimelli, M., of liver tumours.
Craw, W., Doci, R., Repetto, M. & Simoni, I. Performance comparison between a totally
G. (1986) Regional implantable pump
and a conventional access system. Eur. J. Swg. Oncol. 12: 277-282. 4. Cumberlin, R., De Moss, E., Lassos, M. & Friedman, M. (1985) Isolation perfusion for malignant melanoma of the extremity: a review. J. Clin. Oncol. 3: 1022-I 03 1. 5. Cunliffc, W. J. & Sugarbaker, P. H. (1989) Gastrointestinal malignancy: rationale for adjuvant therapy using early postoperative intraperitoneal chemotherapy. Br. J. Surg. 76: 1082-1090. 6. Dimitrakopoulou, A., Frohmiiller, (PET) trHgt zur Individualisierung metastasen bei. Langenbecks Arch.
S., Strauss, L. G. & Schlag, P. (1989) Positronenemissionstomographie einer regionalen Tumortherapie bei Patienten mit colorectalen Leber(Suppl.) Chir Forum: 497-502.
REGIONAL 7. Ensminger,
W. D. & Gyves,
8. Franklin, Welvaart,
J. W.
H. R., Schraffordt K., van der Velden,
(1984)
CHEMOTHERAPY Regional
Koops, H., J. W., van
Hart, A. A. M. & Riimke, P. (1988) evaluate the effect of adjuvant isolated
Il.
chemotherapy.
Oldhoff, J., C zarnetzki, Dijk, E., van der Esch,
6: 701-708. drug delivery.
Cancer Treat.
B. M., Macher, E. P., Oosterhuis,
To perfuse or not to perfuse? regional perfusion in patients
a thickness of 1.5 mm or greater. J. Clin. Onol. 9. Freeman, A. I. & Mayhew, E. (1986) Targeted 10. Ghussen, regional
cancer
181 Rep. 68: 101-l
A retrospective comparative study to with stage I extremity melanoma with
Cancer 58: 5733583.
F., Nagel, K., Groth, W., Miiller, J. M. & Stiitzer, H. (1984) A prospective randomized extremity perfusion in patients with malignant melanoma. Ann. Surf. 200: 764768.
Hohenberger, P., Schlag, P., Herrmann, metastases of colorectal cancer that were
15.
E., Kroon, B. B. R., J. W., Huisman, S. J.,
R. & R&h, U. (1989) Intrahepatic progressive under previous systemic
study
of
5-FU retreatment of liver chemotherapy. Am. J. Clin.
Oncol. 12 (5): 447-452. 12. Hohn, D. C., Stagg, R. J., Friedman, M. A., Hannigan, J. F., Rayner, A., Ignoffo, R. J., Acord, P. & Lewis, B. J. (1989) A randomized trial of continuous intravenous versus hepatic intraarterial floxuridine in patients with colorectal cancer metastatic to the liver: the Northern California Oncology Group Trial. J. Clin. Oncol. 7: 1646-1654. 13. Hottenrott, C. & Lorenz, M.
(1988)
Implantierbare
Katheter,
Port-
und
Pumpensysteme.
Akt.
Chir.
23:
143-150. 14. Klaase, (1989)
J. M., Results
extremities. 15. Krementz,
Kroon,
B. B. R., Benckhuijsen,
of regional
isolation
Cancer 64: 616-621. E. T. (1986) Regional
16. Lokich, J. & Ensminger, Oncol. lo: 191-198.
W.
C., van
perfusion perfusion,
(1983)
with Current
Ambulatory
Geel,
A. N., Albus-Lutter,
cytostatics
in patients
sophistication,
pump
infusion
what devices
C. E. & Wieberdink,
with next?
soft
tissue
tumors
J. of the
Cancer 57: 416432.
for hepatic
artery
infusion.
Seminar
17. Manner, isolierten
M., Sinn, H., Bubeck, H. & Schlag, P. (1990) Cytostatikaperfusion van Extremitatentumoren.
Verbesserte Langenbecks
18. Metzger, Mueller,
U., W.,
Bissat, A., Egeli, R., Laffer, U., Martinoh, S., for Clinical Cancer Research (SAKK) (1987)
Mermillod, Schroeder,
B., Aeberhard, R. & Weber,
Intraportal chemotherapy in colorectal 19. Ridge, J. A., Bading, J. R., Gelbard,
W.
P., Gloor, F., (Swiss Group
carcinoma as an adjuvant modality. A. S., B enua, R. S. & Daly, J. M.
hepatic metastascs. Cancer 59: 154771553. 20. Safi, F., Bittner, R., Roscher, R., Schuhmacher, for
hepatic
metastases
of
colorectal
K., Gaus,
carcinoma
W. & Beger,
(continuous
arterial/intravenous therapy). Cancer 64: 379-387. 21. Semmler, W., Gademann, G., Schlag, P., Bachert-Baumann, (1988) Impact of hyperthermic regional perfusion therapy monitored 22. 23.
by “‘P MR
spectroscopy.
Mapetic
P., Dorsam, chemotherapy
J.,
Regional versus
P. & Herfarth,
chemotherapy
continuous
27.
Schlag,
28.
F., eds, European Handbook Schlag, P. & Hohenberger,
C. (1989)
29.
Domellof, L., ed. Drug Delivq Schlag, P., Strauss, L. G.
Liver
of Surgical
Regionale infusion
Oncology, P. (1989) The
Imagin,q 6: 335-340.
chemotherapy
Rationale
and
Chemotherapie
uptake R.,
prerequisites
for
chemotherapy.
van
In: Veronesi,
in Cancer Treatment, ZZ, pp. 43353. Berlin: Springer & Semmler, W. (1989) Klinische Anwendung (PET) Se&r,
Eine
infusion Eur. J.
SituationsL., Mazzeo,
of liver
cancer.
In:
Verlag. van Magnet-Resonanz-
in der Onkologie.
M. J., Gerneth,
for
at home.
arterial tumors.
J., Denis,
P. &
adjuvant
treatment
Lcbertumoren-m U., Burn,
following
Schlag,
as a surgical
pp. 1888199. Berlin: Springer Verlag. rationale of intraarterial chemotherapy
Spektroskopie (MRS) und Positronen-Emissions-Tomographie 162-163. 30. Schlag, P., Saeger, H. D., Friedl, P., Kettelhack, Ch.,
intra-
P., Zabel, H.-J., Lorenz, W. & van Kaick, G. on cell metabolism of malignant melanoma
Aguiar, J. L. A., Bartkowski, R. & Berger, M. (1988) Hepatic proves to be advantageous in the treatment of experimental liver
Cancer Clin. Oncol. 24: 1013-1018. Schlag, P. & Hohenberger, P. (1988) analyse. Chirq 59: 218-224.
bei der
J. Surg. 11: 452-458. Perfusion of colorectal
G. H. (1989)
intraarterial
intraperitoneal 1: 66-79.
Schlag, P. (1985) Continuous cancer chemotherapy. Int. J. Technol. Assessment Health Care 1: 343-35 1.
25. Schlag, (HAI) 26.
Resonnncr
World (1987)
Sigurdson, E. R., Ridge, J. A., Kemeny, N. & Daly, J. M. (1987) Tumor and liver drug hepatic artery and portal vein infusion. J. Clin. Oncol. 5: 1836-1840. Sugarbaker, P. H., Cunliffe, W., Belliveau, J. F., DeBruijn, E. A., Graves, T., Mullins, Gianola, F. (1988) Rationale for perioperative gastrointestinal malignancy. Reg. Cancer Treat.
24.
intraoperative Leckkontrolle Arch 375: 208-213.
Th.,
Gastroentcrology Trede,
M.,
Herfarth.
24:
P. SCHLAG
182 Ch.
(1990)
Therafiy
Adjuvant
qf Cancer.
intra
Philadelphia:
FUDR-rhemotherapy
in colon
31. Stehlin, J. S., Greeff, P. J., de Ipolyi, P. D., Giovanella, Williams, L. J., Natelson, E. A. & Anderson, R. F. (1988) melanoma: 32. Stephens,
an immune F. 0. (1988)
1: 4-10. 33. Stephens, F. O., Waugh, delivery of intra-arterial
cancer
patients.
of adjuvant
portal
stimulant? Houston Med. J. 4: 61-82. Why use regional chemotherapy? Principles R. C. & Prest, G. (1988) chemotherapy. Reg. Cancer
vein
Salmon,
S. E. rd.
B. C., Klein, G., McGaff, C. J. Jr., Heat as an adjuvant in the treatment
Radiological
Treat.
and pharmacokinetics.
&uunn!
versus
cytotoxic
perfusion
in colorectal
Davis, B. R., of advanced
Reg. Cancer Treat.
surgical
placement
van
Lebrrmetastasen:
of cannulas
for
1: 37-43.
34. Strohmeyer, T., Haugeberg, G. & Lierse, W. (1986) Vaskularisation rosionsanatomische Studie. Acta Amt. 126: 172-l 76. 35. Taylor, I., Machin, D., Mullee, M., Trotter, G., Cooke, T. & West, trial
In:
Saunders.
cancer.
C. (1985)
A randomized
BY. J. Surg. 72: 359-363.
eine
kor-
controlled
Treatment
Reviews
(1990)
17, 177-182
Regional chemotherapy: techniques and clinical
different results
operative
P. Schlag Section of Surgical
Oncology, Department
Principal
of Surgery, University of Heidelberg,
considerations
for
regional
F.R.G.
chemotherapy
Most malignant solid tumors ifnot initially resistant, become unresponsive to conventional cytotoxic cancer therapy. Dose limiting side-effects contribute to the drug resistance of these tumors, but regional drug administration might overcome some of the disappointments of systemic cytotoxic chemotherapy (7, 9). Th e rationale of regional cancer chemotherapy is to use the direct approach to the tumor and thus to increase the drug concentration locally without a compromising systemic toxicity. For regional therapy of primary or secondary liver tumors, decreased systemic toxicity might be expected to be due to the metabolic activity of normal liver tissue since most drugs are metabolized in passing through the liver to the general circulation (22, 32). This first pass effect increases the possibility of administering a higher cytotoxic dose regionally than is possible by using an intravenous route. Similarly, with isolated organ perfusion a complete separation between body and tumor-bearing organ circulation is achieved (15). Due to the great technical effort and the risks involved in isolated organ perfusion, as well as other problems such as the inability ofrepeating this approach in the same patient, at present the technique is used mainly for malignant tumors of the extremities. Also, regional infusion techniques have become increasingly popular in the last few years with intraperitoneal drug administration a promising therapeutic strategy (2, 5). Most experience with regional chemotherapy is derived from primary and secondary liver tumors where it is necessary to distinguish between intra-arterial and intraportal treatment. Intra-arterial
chemotherapy
of malignant
liver
tumors
The theory behind intra-arterial chemotherapy of malignant liver tumors is the fact that these tumors normally take their blood supply from the hepatic artery (19, 22, 34). To achieve a sustained approach to the hepatic artery, an operative catheter insertion is better than repeated catheter placement by interventional radiologic techniques (33); the latter technique is compromised by a high rate of thrombosis and infections. To circumvent hepatic artery occlusion during operative catheter placement, the gastro-duodenal artery is used. A catheter positioned in this branch of the common hepatic artery does not interfere with blood flow, but ensures constant direct drug administration (27). Unfortunately, in about 50% of all patients the liver is vascularized by two or three different branches of hepatic arteries and insertion of more than one catheter is necessary in these cases to obtain 030557372/90/2&3177+06
$03.00/0
0 177
1990 Academic
Press Limited
178
P. SCHLAG
complete liver perfusion by the cytostatic drug. In principle, the implanted catheter can be connected to a completely implantable medication pump or to an injection port; both can be implanted subcutaneously and enable a direct approach to the catheter. Drug administration is directly via the implanted pump and can be given to patients with injection ports using an external pump system. There has been much discussion on the advantages and disadvantages ofport and implanted pump systems (13, 16,24). Implanted pumps are more comfortable for patients and have a low risk of thrombosis and infections. On the other hand, the implantable pumps are extremely expensive and are rather inflexible as regards drugs that can be used, drug volumes and infusion rate. Therefore, increasing numbers of port systems in combination with external pump systems are being used (3). Of greater importance is the effectiveness of intra-arterial chemotherapy. Most prospective and randomized studies have been carried out in patients with metastatic colorectal cancer. These studies have compared intra-arterial with standard intravenous chemotherapy. Most of these studies showed a clear advantage for intra-arterial chemotherapy judged on the response to treatment (26, 28). There is a significantly higher rate of tumor regressions with intra-arterial chemotherapy than with intravenous treatment. Unfortunately, this higher response rate does not result in an increase in survival. This can be partially explained by extra-hepatic recurrences. In some studies therefore intraarterial and intravenous chemotherapy were combined (12, 20). There is no evidence, however, that this technique is of any advantage. In summary, the principal advantage of regional chemotherapy compared to systemic treatment is a greater response rate but few patients profit from this due to extra-hepatic tumor spread. In future, our aim must be to find better selection criteria for patients who can benefit from intra-arterial drug administration. We have found that intra-arterial retreatment of patients who previously failed to respond to systemic chemotherapy is worthwhile (11); they had a much better prognosis than patients who were not retreated intra-arterially. This approach is clinically feasible but not satisfactory in principle. Better methods are required which allow a more precise identification between those who will and those who will not profit from intraarterial chemotherapy. One method to achieve this may be by positron emission tomography (29). This method is based on metabolism measurements in vivo. Using ‘*F-uracil, the drug accumulation in normal and tumor tissue can be calculated over time. Our experience shows that in some patients a clear advantage of intra-arterial in comparison to intravenous drug accumulation can indeed be visualized (6). In our clinic the percentage of patients who showed a higher drug accumulation in the tumor tissue after intra-arterial in comparison to intravenous therapy is rather low. Nevertheless, this method permits selection of patients who may profit from chemotherapy and those who will not. Since ‘*F-uracil imaging can calculate only drug accumulation in relation to different administration modes, the results of chemoresponsiveness can be biased by drug anabolism or catabolism. Magnetic resonance spectroscopy is a new method with which we were able to demonstrate for the first time that different metabolic pathways of 5-FU can be measured in vivo in the patient (21). Therefore, in the future this method will hopefully contribute to a better understanding of the possibilities and indications for regional chemotherapy. Intraportal There are some reports tumors. In comparison
chemotherapy
of malignant
liver
tumors
on the efficacy of intraportal chemotherapy for malignant to the intra-arterial route, however, none of these studies
liver dem-
REGIONAL
CHEMOTHERAPY
179
onstrated a clear advantage of the intraportal route, neither for response rates nor for survival (26). In animal experiments, intraportal chemotherapy even showed a significant disadvantage compared to intravenous or intra-arterial administration (25). Intraportal chemotherapy is therefore not to be recommended for the treatment of manifest malignant liver tumors. On the other hand, we know that tumor cells, especially those from colonic cancer, spread via the mesenteric vein through the portal system into the liver. To attack these floating or microscopic invasive tumor cells is the rationale behind using intraportal chemotherapy as adjuvant therapy after curative tumor resection in colon cancer patients 118). This concept seems reasonable and has become popular since a first study seemed to confirm the theory in practice (35). Unfortunately, some later studies failed to confirm these results or were inconclusive. In our own study, we have not been able to demonstrate a significant reduction of liver metastases in patients who underwent intraportal chemotherapy following curative colon cancer resection compared to patients who were treated only surgically (30). Therefore, the assumption that adjuvant intraportal chemotherapy is of value to patients with colorectal cancer is as yet unproven and subject to further investigation.
Intraperitoneal
chemotherapy
It is well known that some tumors such as ovarian carcinomas or gastric cancers spread predominantly to the peritoneal cavity. To destroy these tumor cells directly by intraperitoneal drug instillation seems an attractive idea. Since practicable catheter systems for intraperitoneal chemotherapy have been developed recently, this technique has become more popular in clinical practice. Nevertheless, due to practical difficulties concerning adequate intraperitoneal drug distribution, the definition of optimal therapeutic indications has lagged behind the theoretical knowledge about this therapy (5). This may be an explanation for the fact that convincing data on the advantages of intraperitoneal drug administration in comparison to conventional treatment modalities are not yet available. Since gastrointestinal tumors also spread intraperitoneally via the mesenteric vein, intraperitoneal chemotherapy has been used as an adjuvant treatment (23). The rationale is to achieve a high drug concentration in the peritoneal cavity as well as in the portal system as a result of peritoneal drug absorption. The preliminary data are encouraging, although the results obtained in small cohorts of patients need confirmation.
Isolated
limb
perfusion
chemotherapy
An artificial circuit can be established by means of a heart-lung machine and a surgical approach to the main vascular structures of the extremities. Since all the other important organs or organ systems can be excluded from this artificial blood circuit, high dose chemotherapy in the tumor-bearing extremity can be used (15). A tourniquet between the extracorporeal and the normal systemic blood circuit helps to prevent drug reflux. This time- and personnel-consuming sophisticated surgical technique has become the standard procedure for the treatment of recurrent malignant melanoma and advanced soft-tissue sarcoma of the extremities. In about 6076 of patients, complete tumor regression in cases with satellitosis or in-transit metastases can be expected (1, 4). The most active substance commonly used for isolated limb perfusion in malignant melanoma is melphalan.
180
P. SCHLAG
The activity can be increased if hyperthermic perfusion is used (31). Since cytostatic extremity perfusion was introduced into the treatment of locally advanced or recurrent malignant melanoma, amputation is generally no longer indicated. The importance of isolated limb perfusion for primary adjuvant treatment after surgical removal ofadvanced primary lesions is questionable (4, 8). There are, however, many studies which support the concept ofadjuvant hyperthermic limb perfusion in patients with high-risk melanoma. In our study also the 5-year recurrence-free survival of perfused high-risk melanoma patients is much better than historical control figures from the literature (17). There is at present one small randomized study which found statistically significant activity of adjuvant limb perfusion in comparison to surgery alone, but this trial is open to a number of criticisms (10). To answer the question of whether isolated limb perfusion is of any value for patients with high-risk malignant melanoma we await the results of a randomized intergroup study of the E.O.R.T.C. and W.H.O. Apart from advanced malignant melanoma of the extremities, isolated cytostatic limb perfusion is also of benefit in patients with advanced soft-tissue sarcomas of the extremities (14). The aim of a preoperative extremity perfusion is to reduce tumor volume by killing the tumor cells. This would be a prerequisite for limb-sparing operations even in advanced or recurrent sarcomas. In our experience, as well as in reported results from the literature, isolated limb perfusion does help prevent limb amputation in a considerable number of patients without affecting local recurrence and overall survival. Like most effective treatments isolated limb perfusion is not without side-effects, but these are not hematological or gastrointestinal if adequate intraoperative monitoring for leakage control is available. In our hands, indium-labelled autologous erythrocytes represent the most effective procedure for leakage control (17), but in almost all cases we expect to see erythema and sometimes neurologic disturbances, especially if cisplatin is used under hyperthermic conditions. These local side-effects can probably be reduced if individualized drug dosages according to the chemosensitivity of the tumor are administered. Unfortunately, up to the present, no practical method was available to monitor drug effects in vivo during isolated limb perfusion. Magnetic resonance spectroscopy offers this possibility by measuring high-energy phosphates and pH (21). Thus, a guideline for cell necrosis due to the cytostatic treatment could be established. We believe that based on all these new techniques and methods, regional chemotherapy can be much more individualized and concomitantly its efficiency will be improved.
References 1. Baas, P. C., Schraffordt Koops, H., Hoekstra, H. J., Oosterhuis, J. W., van der We&, L. T. & Oldhoff, J. (1988) Isolated regional perfusion in the treatment of local recurrence, satellitosis and in-transit metastases of melanomas of the extremities. Reg. Cancer Trent. 1: 33-36. 2. Brenner, D. E. (1986) Intraperitoneal chemotherapy: a review. J. Clin. Oncol. 4: 1135-l 147. 3. Civalleri, D., Cafiero, arterial chemotherapy
F., Cosimelli, M., of liver tumours.
Craw, W., Doci, R., Repetto, M. & Simoni, I. Performance comparison between a totally
G. (1986) Regional implantable pump
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